Tuberculosis (TB) is the leading cause of death in HIV-infected patients. Highly active antiretroviral therapy (HAART) during TB treatment confers substantial survival benefit, but is complicated by complex drug-drug interactions and frequent toxicities. HAART is already complicated by inter-individual variability in efficacy and toxicities, due at least in part to variable antiretroviral drug pharmacokinetics. Interindividual differences in responsive to interactions between HIV and TB drugs are likely to exacerbate the variable treatment responses. Increased understanding of the mechanisms underlying inter-individual differences in drug-drug interactions is necessary for management of such interactions and optimized treatment outcomes in HIV/TB co-infected patients. The long-term objective of our research is to improve the management of drug-drug interactions in HIV/TB co-infected patients through enhanced understanding of the predictors and mechanisms of such interactions. This proposal will focus on the genetic and non-genetic predictors of severe drug-drug interactions in HIV/TB co-infected patients. Our overarching hypothesis is that inherent differences in inducibility or inhibition of genetic variants of HAART-associated drug metabolizing enzymes (DMEs) and drug transporters profoundly affect drug-drug interactions. We propose that previous pharmacokinetic studies have underestimated the severity of these interactions and the associated risk for treatment failure in individual patients depending on biologic and genetic factors. Our hypotheses will be pursued through three specific aims. Aim 1 will test the hypothesis that the effect of rifampin-containing anti-TB therapy on efavirenz plasma pharmacokinetics differs fundamentally among CYP2B6 extensive and intermediate metabolizers as compared to CYP2B6 slow metabolizers. Aim 2 will test the hypothesis that one (or more) of the components of the 4- drug first-line anti-TB therapy preferentially inhibits one (or more) of the efavirenz metabolism accessory pathways in CYP2B6 slow metabolizers. Aim 3 will explore the hypothesis that rifampin-containing anti-TB therapy reduces the intracellular concentrations of nucleoside reverse transcriptase inhibitors. Successful completion of the proposed studies will generate fundamental knowledge regarding drug-drug interactions during concomitant HIV/TB therapy, providing insights into inter-individual differences in drug-drug interactions. Such evidence is essential to rational HAART prescribing in HIV/TB co-infected patients, and will provide a mechanism to accelerate the translation of pharmacogenomic information into clinical practice.